Isosulfan Blue, chemically known as N-[4-[4-(diethylamino)phenyl]2,5-disulfophenyl)methylene]2,5-cyclohexadien-1-ylidine]-N-ethylethanaminium sodium salt is represented by Formula (I) and marketed under the brand name LYMPHAZYRIN.

Isosulfan blue is a triaryl methane dye used as a cancer diagnostic agent. It is a structural isomer of sulfan blue and belongs to family of triaryl methane dyestuffs.
Most of the currently available preparation methods of triaryl methane dyestuffs involve oxidation of leuco/isoleuco acids as well as leuco/isoleuco bases. The oxidation is carried out by using potassium dichromate, lead dioxide, oxone and chloranil.
U.S. Pat. No. 1,531,507 discloses a process of making intermediate of Isosulfan blue, namely, benzaldehyde-2,5-disulfonic acid. The process involves sulfonation of 2-chloro benzaldehyde using 23% and 65% oleum and neutralization using sodium carbonate to obtain 2-chloro benzaldehyde 5-sulfonic acid, which on treatment with sodium sulfite and sodium bisulfite at reflux temperature and acidifying the reaction mixture using sulfuric acid to obtain Benzaldehyde-2, 5-disulfonic acid. Said method involves tedious neutralization, basification and acidification thus being commercially unviable.
U.S. Pat. No. 4,330,476 discloses a process for making of triaryl methane dyestuff, which involves condensation of benzaldehyde derivative with N,N-Diethyl aniline and urea in glacial acetic acid at 100° C. and in situ oxidation using chloranil and intensive gassing with air. A total mixture of nitrogen oxide and nitrogen dioxide produced by treating sodium nitrite with sulfuric acid is metered into reaction mixture and after completion of reaction evaporation of acetic acid gives dyestuff. This method of preparation generates hazardous gases besides impurity formation, which adversely impacts the yield and purity thus being unviable on commercial scale.
U.S. Pat. No. 5,659,053 discloses a process for the preparation of Sulfan Blue, which involves oxidation of leuco acid in presence of oxygen transfer catalyst that contains complexed heavy metal ion using hydrogen peroxide, hydrogen peroxide donor compound, an organic hydroperoxide or percarboxylic acid as oxidizing agents and oxygen transfer catalyst used as a class of porphyrins, tetraaza[14]annulenes, phthalocyanines or tetraazacyclotetradecanes in water. This method involves costly catalysts and thus being not very feasible on large scale.
U.S. Pat. No. 1,805,925 disclosed a process for preparation of triaryl methane dyestuff, which involves oxidation of leuco acid using copper salt in pyridine and water mixture at 80-120° C. The copper salts used as cupric chloride, cuprous chloride, cupric sulphate. This method of preparation involves use of pyridine, which is not a suitable solvent and thus reaction is carried out at high temperature. Such reaction conditions leads to formation of impurities and causes low yield and low purity.
U.S. Pat. No. 2,726,252 discloses a process for preparation of leuco triaryl methane compound involving condensation of benzaldehyde derivatives with arylamine using auxiliary agent selected from urea, thiourea, their lower alkyl derivatives at 70-120° C. in alcohol using acids selected from hydrochloric, sulfuric, phosphoric, formic, mono-, di- or tri-chloro acetic, benzene sulfonic, p-toluene-sulfonic.
U.S. Pat. No. 7,534,911 has disclosed process for preparation of Isosulfan blue in which first step involves sulphonation of 2-chloro benzaldehyde with a sulphonating agent to obtain 2-chloro benzaldehyde 5-sulfonic acid and treating 2-chloro benzaldehyde 5-sulfonic acid with sodium sulphite and subsequent basification to obtain benzaldehyde-2,5-disulfonic acid disodium salt. Condensation of benzaldehyde-2,5-disulfonic acid disodium salt with N, N-diethyl aniline using hydrochloric acid to obtain Isoleuco acid disodium salt. Oxidation of Isoleuco acid di sodium salt with ammonium dichromate under acidic condition gives Isosulfan Blue. In this method of preparation, oxidation reaction is carried out under acidic condition by using ammonium dichromate which generates desethyl impurity in large amount and it is difficult to remove this impurity by purification or recrystallization. Even after several purification desethyl impurity remain greater than pharmaceutical acceptable limit of known impurities. Further use of ammonium dichromate under acidic conditions is hazardous.
U.S. Pat. No. 7,662,992 discloses a process for preparation of Isosulfan blue, which involves sulfonation of 2-chloro benzaldehyde and replacement of chloride with an alkali metal sulphite/bisulphite at elevated temperature under closed conditions. This reaction is carried out in a parr pressure vessel equipped with overhead magnetic stirring. The reaction mixture in the vessel was stirred and heated to 170-180° C. for 5-7 hours generating 140-150 psi pressure. Another step involves condensation with N, N-diethyl aniline and urea in glacial acetic acid to obtain isoleuco acid and then oxidation of isoleuco acid with silver oxide in a polar solvent to obtain isosulfan blue acid. In the oxidation reaction large amount of silver oxide is used. In the example disclosed 2.5 molar equivalent of silver oxide is used. During oxidation considerable amount of desethyl impurity is formed, Isosulfan blue free acid was obtained by adjusting the pH to acidic and adding isopropyl ether as anti-solvent, it was then converted into sodium salt by adjusting pH more than 6.0 with sodium carbonate and then purified with aqueous Isopropyl alcohol/Acetone.
This method of preparation requires 170-180° C. temperature with generating pressure 140-150 psi which is very risky in bulk scale. Also this process involves use of large amount of costly silver oxide as oxidizing agent. This process utilized very large amount of flammable solvent like di-isopropyl ether. The oxidation under these condition leads to the formation of Des ethyl impurity thus requiring several steps of purification and results in low yield.
The yield of isosulfan blue prepared by the preceding processes particularly by that of U.S. Pat. No. 7,662,992 was below 20% and the purity of isosulfan blue obtained by following U.S. Pat. No. 7,534,911 was below 80%.
Therefore, there is a need for an improved process for preparation of isosulfan blue free of desethyl impurity and suitable for large scale production besides having better purity and yield.